The long term objective of this proposal is to clarify the relationship between the molecular conformation and OSAR's of an important class of cardiovascular drugs known as calcium entry blockers or calcium channel antagonists. X-ray diffraction methods will be employed to obtain molecular conformational data for a number of these drugs. Immediate attention will be focused on a series of 1,4-dihydropyridine analogs related to the important anti-anginal drug nifedipine. Particular interest will be directed to the unsymmetric ester analogs of nifedipine which display pronounced tissue selectivity with regard to the inhibition of excitation-contraction coupling of cardiovascular tissue. Specific compounds to be investigated include nitrenedipine, which lowers elevated peripheral vascular resistance; nimodipine, which effects cerebral vasodilation without a substantial decrease in blood pressure; and nisoldipine, a potent femoral vasolilator which additionally inhibits thromboxan synthetase and protects against arachidonate-induced suddent death by preventing platelet-induced pulmonary thrombosis. The X-ray cystallographic molecular conformations of these drugs will be examined in relation to OSAR's which specify drug inhibitory potency as a function of the steric minimum width verloop parameter of the aryl ring substituents and tissue selectivity as a function of the steric and lipophilic characteristics of the ester groups. Attempts will be made to relate these concepts to the degree of dihydropyridine ring plane. Two series of six aryl ring derivatives of nimodipine and nisoldipine will be examined in this study.